EP1485098A1 - Pharmaceutical compositions comprising 2-(4-ethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine in nanoparticulate form - Google Patents

Pharmaceutical compositions comprising 2-(4-ethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine in nanoparticulate form

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Publication number
EP1485098A1
EP1485098A1 EP03706615A EP03706615A EP1485098A1 EP 1485098 A1 EP1485098 A1 EP 1485098A1 EP 03706615 A EP03706615 A EP 03706615A EP 03706615 A EP03706615 A EP 03706615A EP 1485098 A1 EP1485098 A1 EP 1485098A1
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EP
European Patent Office
Prior art keywords
pharmaceutical composition
compound
present
phenyl
nanoparticulate form
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Granted
Application number
EP03706615A
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German (de)
French (fr)
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EP1485098B1 (en
Inventor
Jonathan GlaxoSmithKline APPLEBY
Martin Rolfe GlaxoSmithKline HILL
Simon Joseph GlaxoSmithKline HOLLAND
Stephanie Lynn GlaxoSmithKline PEARSON
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Glaxo Group Ltd
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Glaxo Group Ltd
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to certain novel pharmaceutical compositions comprising a selective cyclooxygenase-2 inhibitor, processes for their preparation, methods of treatment of cyclooxygenase-2 mediated diseases comprising administering such compositions to a subject, and to the use of such compositions in the manufacture of medicaments.
  • WO99/12930 discloses 2-(4-ethoxy-phenyl)-3-(4-methanesulfonyl- phenyl)-pyrazolo[1 ,5-b]pyridazine (I) as a potent and selective inhibitor of cyclooxygenase-2 (COX-2).
  • Dissolution testing is a well established technique for obtaining a correlation between in vitro and in vivo data in relation to compound bioavailability.
  • Preliminary dissolution experiments employing compound (I) in micronised form predicted it to be poorly bioavailable.
  • WO01/41760 discloses that the bioavailability of selective COX-2 inhibitory drugs of low water solubility may be enhanced by reducing the drug particle size, such that a substantial proportion are smaller than 1 ⁇ m.
  • a pharmaceutical composition comprising a 1 :1 ratio of compound (I) and hydroxypropylmethylcellulose-acetyl succinate (HPMC-AS) as an amorphous dispersion has been administered to man at 35mg o.d.
  • the resulting pharmacokinetic parameters such as the maximum blood serum concentration of the drug (C max ), the time to achieve the maximum blood serum concentration of the drug (T max ) and the exposure of the volunteer to the drug as measured by the area under the plasma concentration versus time curve (AUC) were all conducive to the further development of compound (I).
  • C max maximum blood serum concentration of the drug
  • T max time to achieve the maximum blood serum concentration of the drug
  • AUC area under the plasma concentration versus time curve
  • the problem of high inter-subject variability for the parameters C m a ⁇ , T ma ⁇ and AUC may be solved by providing a pharmaceutical composition comprising compound (I), wherein the drug is present in nanoparticulate form.
  • the invention thus provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I)
  • a pharmaceutical composition as defined hereinabove results in significantly reduced inter-subject variability for both C max , T max and AUC when dosed in human volunteers. Furthermore, and contrary to expectation, this pharmaceutical composition resulted in a pharmacokinetic profile in man with a shorter T max , a higher C max and a higher AUC in comparison with the pharmacokinetic profile for the composition comprising a 1 :1 ratio of compound (I) and hydroxypropylmethylcellulose-acetyl succinate (HPMC-AS) as an amorphous dispersion.
  • HPMC-AS hydroxypropylmethylcellulose-acetyl succinate
  • nanoparticulate is defined as solid particles with a median size by volume [D(v,0.5)J in the range 0.4 to 1.8 ⁇ m.
  • compound (I) is present in solid particles with a D(v,0.5) in the range 0.4 to 1.5 ⁇ m.
  • compound (I) is present in solid particles with a D(v,0.5) in the range 0.45 to 1.05 ⁇ m.
  • compound (I) is present in solid particles with a D(v,0.5) of 0.8 ⁇ m.
  • the particle size of the solid particles of compound (I) may be determined by laser diffraction.
  • a suitable machine for determining particle size by laser diffraction is a Sympatec laser diffraction unit, using an HELOS optical bench fitted with a QUIXEL dispersion unit.
  • the median size by volume [D(v,0.5)] of the particles is determined by laser diffraction, as defined above.
  • Numerous processes for the synthesis of solid particles in nanoparticulate form are known. Typically these processes involve a milling process, preferably a wet milling process in the presence of a surface modifying agent that inhibits aggregation and/or crystal growth of the nanoparticles once created. Alternatively these processes may involve a precipitation process, preferably a process of precipitation in an aqueous medium from a solution of the drug in a non-aqueous solvent.
  • the present invention provides a process for preparing compound (I) in nanoparticulate form as hereinbefore defined, which process comprises milling or precipitation.
  • Such processes may be readily adapted for the preparation of compound (I) in nanoparticulate form. Such processes form a further aspect of the invention.
  • the process of the present invention preferably uses a wet milling step carried out in a mill such as a dispersion mill in order to produce a nanoparticulate form of the compound.
  • the present invention may be put into practice using a conventional wet milling technique, such as that described in Lachman et al., The Theory and Practice of Industrial Pharmacy, Chapter 2, "Milling" p.45 (1986).
  • PCT/EP01/07085 SmithKline Beecham pic
  • nylon polyamide
  • internal lubricants for use in the preparation of solid particles of a drug substance in nanoparticulate form.
  • the present invention provides a process for preparing compound (I) in nanoparticulate form comprising wet milling a suspension of compound (I) in a mill having at least one chamber and agitation means, said chamber(s) and/or said agitation means comprising a lubricated nylon, as described in PCT/EP01/07085.
  • the suspension of compound (I) for use in the wet milling is typically a liquid suspension of the coarse compound in a liquid medium.
  • suspension is meant that the compound is essentially insoluble in the liquid medium.
  • Representative liquid media include an aqueous medium.
  • the average particle size of coarse compound (I) may be up to 1 mm in diameter. This advantageously avoids the need to pre-process the compound.
  • the aqueous medium to be subjected to the milling comprises compound (I) present in from about 1% to about 40% w/w, preferably from about 10% to about 30% w/w, more preferably about 20% w/w.
  • the aqueous medium may further comprise one or more pharmaceutically acceptable water- soluble carriers which are suitable for steric stabilisation and the subsequent processing of compound (I) after milling to a pharmaceutical composition, e.g. by spray drying.
  • Pharmaceutically acceptable excipients most suitable for steric stabilisation and spray-drying are surfactants such as poloxamers, sodium lauryl sulphate and polysorbates etc; stabilisers such as celluloses e.g. hydroxypropylmethyl cellulose; and carriers such as carbohydrates e.g. mannitol.
  • the aqueous medium to be subjected to the milling may further comprise hydroxypropylmethyl cellulose (HPMC) present in from about 0.1 to about 10% w/w, preferably in about 5% w/w in the aqueous medium to be subjected to the milling.
  • the aqueous medium to be subjected to the milling may further comprise hydroxypropylmethyl cellulose (HPMC) present in about 3% w/w or 1% w/w.
  • the aqueous medium to be subjected to the milling may further comprise mannitol present in from about 1 to about 15% w/w, preferably in about 10% w/w, in the aqueous medium to be subjected to the milling.
  • the aqueous medium to be subjected to the milling may further comprise sodium lauryl sulphate present in about 0.2% w/w.
  • the process of the present invention may comprise the subsequent step of drying compound (I) to yield a powder.
  • the present invention provides a process for preparing a pharmaceutical composition as hereinbefore defined, which process comprises producing compound (I) in nanoparticulate form optionally followed by drying to yield a powder.
  • drying is meant the removal of any water or other liquid vehicle used during the process to keep compound (I) in liquid suspension or solution.
  • This drying step may be any process for drying known in the art, including freeze drying, spray granulation or spray drying. Of these methods spray drying is particularly preferred. All of these techniques are well known in the art. Spray drying/fluid bed granulation of milled compositions is carried out most suitably using a spray dryer such as a Mobile Minor Spray Dryer [Niro, Denmark], or a fluid bed drier, such as those manufactured by Glatt, Germany.
  • the invention provides a pharmaceutical composition as hereinbefore defined, in the form of a dried powder, obtainable by wet milling solid particles of compound (I) followed by spray-drying the resultant suspension.
  • the pharmaceutical composition as hereinbefore defined further comprises HPMC present in less than 15% w/w, preferably in the range 0.1 to 10% w/w, more preferably in about 5% w/w.
  • the pharmaceutical composition as hereinbefore defined further comprises HPMC present in about 3% w/w or 8% w/w.
  • HPMC present in about 3% w/w or 8% w/w.
  • the pharmaceutical composition as hereinbefore defined, in the form of a dried powder further comprises mannitol present in less than 30% w/w, preferably in the range 1 to 15% w/w, more preferably in about 10% w/w.
  • the pharmaceutical composition as hereinbefore defined in the form of a dried powder, further comprises mannitol present in the range 30 to 45% w/w, more preferably in about 34% w/w or 43% w/w.
  • the pharmaceutical composition as hereinbefore defined in the form of a dried powder, further comprises sodium lauryl sulphate present in about 0.6% w/w.
  • the pharmaceutical composition as hereinbefore defined in the form of a dried powder, further comprises HPMC present in less than 15% w/w, preferably in the range 0.1 to 10% w/w, and mannitol present in less than 30% w/w, preferably in the range 1 to 15% w/w.
  • the pharmaceutical composition as hereinbefore defined in the form of a dried powder, further comprises HPMC present in about 3% w/w, mannitol present in the range 30 to 45% w/w, more preferably in about 34% w/w, and sodium lauryl sulphate present in about 0.6% w/w.
  • HPMC present in about 3% w/w
  • mannitol present in the range 30 to 45% w/w, more preferably in about 34% w/w
  • sodium lauryl sulphate present in about 0.6% w/w.
  • the solid particles of compound (I) obtainable by wet milling, optionally followed by the step of spray-drying, according to the present invention may be presented in a variety of finished formulations including, for instance, tablets, for example swallow tablets, dispersible tablets and chewable tablets; in capsules; aqueous syrups and sachets. These may be prepared by combining the pharmaceutical composition of the present invention with excipients conventionally used in such formulations such as disintegrants, diluents, lubricants, wetting agents, binding agents, flavoring agents, sweeteners, colouring agents, preservatives, suspending agents, coating agents and fillers, and further processing into finished formulations.
  • excipients conventionally used in such formulations such as disintegrants, diluents, lubricants, wetting agents, binding agents, flavoring agents, sweeteners, colouring agents, preservatives, suspending agents, coating agents and fillers, and further processing into finished formulations.
  • compositions of the present invention comprise pharmaceutical compositions as hereinbefore defined, optionally together with one or more excipients such as disintegrants, diluents, lubricants, wetting agents, binding agents, flavoring agents, sweeteners, colouring agents, preservatives, suspending agents, coating agents and fillers.
  • excipients such as disintegrants, diluents, lubricants, wetting agents, binding agents, flavoring agents, sweeteners, colouring agents, preservatives, suspending agents, coating agents and fillers.
  • Representative disintegrants for use in the instant invention illustratively include maize-starch and rice starch, cross-linked N-vinyl-2-pyrrolidinone, sodium starch glycollate, croscarmellose sodium, micrcrystalline or microfine cellulose, low substitued hydroxypropylcellulose (i.e. cellulose partially substitued with 2-hydroxypropyl groups e.g. less than 25% substituted) cross- linked sodium carboxymethylcellulose, swellable ion exchange resins, formaldehyde-casein or alignates.
  • Representative lubricants for use in the instant invention illustratively include a long chain fatty acid, such as stearic acid, or salts thereof, such as magnesium stearate.
  • Representative fillers for use in the instant invention illustratively include silicon dioxide, microcrystalline cellulose, dicalcium phosphate, lactose, sorbitol, stirum carbonate or magnesium carbonate.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising compound (I) in a form which results in a pharmacokinetic profile in a healthy male volunteer study wherein the median T max is in the range 0J5 to 1.25 hours, the median C max is in the range 130 to 170 ng/mL and the AUC (last) is in the range 800 to 900 ng/mL.h.
  • the invention is directed to a method of treating a human or animal subject suffering from a condition which is mediated by COX-2 which comprises administering a pharmaceutical composition comprising compound formula (I) or a pharmaceutically acceptable salt thereof in which the compound is present in solid particles in nanoparticulate form.
  • the invention is directed to the use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof in which the compound is present in solid particles in nanoparticulate form for the manufacture of a medicament for the treatment of a condition which is mediated by COX-2.
  • Example 1 (Pharmaceutical Composition 2) A 1 kg batch of an aqueous suspension containing 20% w/w of 2-(4-ethoxy-phenyl)-3-(4- methanesulfonyl-phenyl)-pyrazolo[1 ,5-b]pyridazine and 5% w/w of hydroxypropylmethylcellulose was passed through a Dena DM-100 bead mill. The single 100ml chamber fabricated from Nylacast Nylube was used in a recirculation configuration with the chamber containing 85% by volume of yttrium stabilised zirconium oxide beads (Tosoh, Japan).
  • the batch was processed using four different bead sizes in sequence: 1mm diameter bead sample, 0.65mm diameter bead sample, 0.4mm diameter bead sample, 0.3mm diameter bead sample.
  • the batch was processed for one hour using each bead sample. The yield was 81.3%.
  • To the finely milled suspension was added 10% w/w mannitol and the resulting suspension subsequently spray- dried to yield Pharmaceutical Composition 2.
  • the product had a median particle size of 1.01 microns as measured by laser diffraction size analysis using a Sympatec laser diffraction unit, with a HELOS optical bench fitted with a QUIXEL dispersion unit.
  • a 5 kg batch of an aqueous suspension containing 20% w/w of 2-(4-ethoxy-phenyl)-3-(4- methanesulfonyl-phenyl)-pyrazolo[1 ,5-b]pyridazine, 0.2% w/w of sodium lauryl sulphate and 1% w/w of hydroxypropylmethylcellulose was passed through a Drais Cosmo 5 bead mill.
  • the single 500ml chamber fabricated from Sustaplast Nylon 6G was used in a recirculation configuration with the chamber containing 570 mL of yttrium stabilised zirconium oxide beads (Tosoh, Japan).
  • the batch was processed using two different bead sizes in sequence: 0.8 mm diameter bead sample and a 0.3 mm diameter bead sample. The batch was processed for 23 minutes for the larger bead size and 80 minutes for the smaller bead size. The yield was 90%. To the finely milled suspension was added 10% w/w mannitol and the resulting suspension subsequently spray-dried to yield Example 2.
  • the product had a median particle size of 0.8 microns as measured by laser diffraction size analysis using a Sympatec laser diffraction unit, with a HELOS optical bench fitted with a QUIXEL dispersion unit.
  • a randomised, open label, crossover comparison between single oral doses of 35mg of each of two pharmaceutical compositions of 2-(4-ethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)- pyrazolo[1 ,5-b]pyridazine was conducted in 24 healthy male volunteers.
  • Single oral doses of 35mg of each of two pharmaceutical compositions of 2-(4-ethoxy-phenyl)-3-(4-methanesulfonyl- phenyl)-pyrazolo[1 ,5-b]pyridazine were administered to fasted volunteers. Seven day intervals separated each dose. The pharmacokinetic characteristics of each pharmaceutical composition were determined over a 48 hour time period.
  • composition 1 Amorphous spray-dried pharmaceutical composition comprising 2-(4-ethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1 ,5-b]pyridazine and hydroxypropylmethylcellulose-acetyl succinate in a 1 :1 ratio produced by conventional spray- drying techniques.
  • Table 1 Summary of Median Serum Derived Pharmacokinetic Parameters for Pharmaceutical Compositions 1 and 2 of 2-(4-Ethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1 ,5- bjpyridazine from a Healthy Male Volunteer Study of 24 Subjects.
  • composition 1 Composition 2
  • composition 1 Composition 2
  • composition 1 Composition 2

Abstract

The invention provides a pharmaceutical composition comprising a compound of formula (I) and pharmaceutically acceptable salts thereof, in which the compound is present in solid particles in nanoparticulate form, in admixture with one or more pharmaceutically acceptable carriers or excipients.

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING 2 - (4-ETH0XY- PHENYL) -3 - (4-METHANESULFONYL-PHENYL) -PYRAZOLO , l , 5-B ! PYRIDAZINE IN NANOPARTICULATE FORM
The present invention relates to certain novel pharmaceutical compositions comprising a selective cyclooxygenase-2 inhibitor, processes for their preparation, methods of treatment of cyclooxygenase-2 mediated diseases comprising administering such compositions to a subject, and to the use of such compositions in the manufacture of medicaments.
WO99/12930 (Glaxo Group Limited) discloses 2-(4-ethoxy-phenyl)-3-(4-methanesulfonyl- phenyl)-pyrazolo[1 ,5-b]pyridazine (I) as a potent and selective inhibitor of cyclooxygenase-2 (COX-2).
Dissolution testing is a well established technique for obtaining a correlation between in vitro and in vivo data in relation to compound bioavailability. Preliminary dissolution experiments employing compound (I) in micronised form predicted it to be poorly bioavailable. As a result attempts were made to improve the bioavailability of compound (I). WO01/41760 (Pharmacia Corporation) discloses that the bioavailability of selective COX-2 inhibitory drugs of low water solubility may be enhanced by reducing the drug particle size, such that a substantial proportion are smaller than 1 μm. However, dissolution experiments using a pharmaceutical composition comprising compound (I), wherein the drug was present in nanoparticulate form, still resulted in a poor dissolution profile, thus predicting this pharmaceutical composition to be poorly bioavailable in man. Further dissolution experiments indicated that the bioavailability of compound (I) could be enhanced by co-formulation with hydroxypropylmethylcellulose-acetyl succinate (HPMC-AS) in an amorphous dispersion. Moreover a 1 :1 ratio of compound (I) and HPMC-AS was found to be optimal.
As a result a pharmaceutical composition comprising a 1 :1 ratio of compound (I) and hydroxypropylmethylcellulose-acetyl succinate (HPMC-AS) as an amorphous dispersion has been administered to man at 35mg o.d. The resulting pharmacokinetic parameters such as the maximum blood serum concentration of the drug (Cmax), the time to achieve the maximum blood serum concentration of the drug (Tmax) and the exposure of the volunteer to the drug as measured by the area under the plasma concentration versus time curve (AUC) were all conducive to the further development of compound (I). However, unacceptably high inter- subject variability was seen for these parameters.
The problem of high inter-subject variability for the parameters Cmaχ, Tmaχ and AUC may be solved by providing a pharmaceutical composition comprising compound (I), wherein the drug is present in nanoparticulate form.
Accordingly, in a first aspect the invention thus provides a pharmaceutical composition comprising a compound of formula (I)
and pharmaceutically acceptable salts thereof, in which the compound is present in solid particles in nanoparticulate form, in admixture with one or more pharmaceutically acceptable carriers or excipients.
Surprisingly, we have now found that a pharmaceutical composition as defined hereinabove results in significantly reduced inter-subject variability for both Cmax, Tmax and AUC when dosed in human volunteers. Furthermore, and contrary to expectation, this pharmaceutical composition resulted in a pharmacokinetic profile in man with a shorter Tmax, a higher Cmax and a higher AUC in comparison with the pharmacokinetic profile for the composition comprising a 1 :1 ratio of compound (I) and hydroxypropylmethylcellulose-acetyl succinate (HPMC-AS) as an amorphous dispersion. Such a pharmacokinetic profile is particularly beneficial for the treatment of acute pain disorders where early and rapid relief from the pain or other symptoms is desired.
For the purposes of the present invention "nanoparticulate" is defined as solid particles with a median size by volume [D(v,0.5)J in the range 0.4 to 1.8 μm. In another aspect of the invention compound (I) is present in solid particles with a D(v,0.5) in the range 0.4 to 1.5 μm.
In another aspect of the invention compound (I) is present in solid particles with a D(v,0.5) in the range 0.45 to 1.05 μm.
In another aspect of the invention compound (I) is present in solid particles with a D(v,0.5) of 0.8 μm.
The particle size of the solid particles of compound (I) may be determined by laser diffraction. A suitable machine for determining particle size by laser diffraction is a Sympatec laser diffraction unit, using an HELOS optical bench fitted with a QUIXEL dispersion unit. As used herein, the median size by volume [D(v,0.5)] of the particles is determined by laser diffraction, as defined above.
Numerous processes for the synthesis of solid particles in nanoparticulate form are known. Typically these processes involve a milling process, preferably a wet milling process in the presence of a surface modifying agent that inhibits aggregation and/or crystal growth of the nanoparticles once created. Alternatively these processes may involve a precipitation process, preferably a process of precipitation in an aqueous medium from a solution of the drug in a non-aqueous solvent.
Accordingly, in a further aspect, the present invention provides a process for preparing compound (I) in nanoparticulate form as hereinbefore defined, which process comprises milling or precipitation.
Representative processes for the preparation of solid particles in nanoparticulate form are described in the patents and publications listed below.
U.S. Patent No. 4,826,689 to Violanto & Fischer U. S. Patent No. 5,145,684 to Liversidge et al
U.S Patent No. 5,298,262 to Na & Rajagopalan
U.S. Patent No. 5,302,401 Liversidge et al
U.S. Patent No. 5,336,507 to Na & Rajagopalan
U.S. Patent No. 5,340,564 to lllig & Sarpotdar U.S. Patent No. 5,346,702 to Na Rajagopalan
U.S. Patent No. 5,352,459 to Hollister et al
U.S. Patent No. 5,354,560 to Lovrecich U.S. Patent No. 5,384,124 to Courteille et al
U.S. Patent No. 5,429,824 to June
U.S. Patent No. 5,503,723 to Ruddy et al
U.S. Patent No. 5,510 118 to Bosch et al U.S. Patent No. 5,518 to Bruno et al
U.S. Patent No. 5,518,738 to Eickhoff et al
U.S. Patent No. 5,534,270 to De Castro
U.S. Patent No. 5,536,508 to Canal et al
U.S. Patent No. 5,552,160 to Liversidge et al U.S. Patent No. 5,560,931 to Eickhoff et al
U.S. Patent No. 5,560,932 to Bagchi et al
U.S. Patent No. 5,565,188 to Wong et al
U.S. Patent No. 5,571 ,536 to Eickhoff et al
U.S. Patent No. 5,573,783 to Desieno & Stetsko U.S Patent No. 5,580,579 to Ruddy et al
U.S. Patent No 5,585,108 to Ruddy et al
U.S. Patent No. 5,587,143 to Wong
U.S. Patent No. 5,591456 to Franson et al
U.S. Patent No. 5,622,938 to Wong U.S. Patent No 5,662,883 to Bagchi et al
U.S. Patent No. 5,665,331 to Bagchi et al
U.S Patent No. 5,718,919 to Ruddy et al
U.S. Patent No. 5,747,001 to Wiedmann et al
International Patent Publication No WO93/25190 International Patent Publication No. WO96/24336
International Patent Publication No. WO 97/14407
International Patent Publication No. WO 98/35666
International Patent Publication No. WO 99/65469
International Patent Publication No. WO 00/18374 International Patent Publication No. WO 00/27369
International Patent Publication No. WO 00/30615 and
International Patent Publication No. WO 01/41760.
Such processes may be readily adapted for the preparation of compound (I) in nanoparticulate form. Such processes form a further aspect of the invention. The process of the present invention preferably uses a wet milling step carried out in a mill such as a dispersion mill in order to produce a nanoparticulate form of the compound. The present invention may be put into practice using a conventional wet milling technique, such as that described in Lachman et al., The Theory and Practice of Industrial Pharmacy, Chapter 2, "Milling" p.45 (1986).
In a further refinement, PCT/EP01/07085 (SmithKline Beecham pic) describes a wet milling procedure using a mill in which at least some of the surfaces are made of nylon (polyamide) comprising one or more internal lubricants, for use in the preparation of solid particles of a drug substance in nanoparticulate form.
In another aspect the present invention provides a process for preparing compound (I) in nanoparticulate form comprising wet milling a suspension of compound (I) in a mill having at least one chamber and agitation means, said chamber(s) and/or said agitation means comprising a lubricated nylon, as described in PCT/EP01/07085.
The suspension of compound (I) for use in the wet milling is typically a liquid suspension of the coarse compound in a liquid medium. By "suspension" is meant that the compound is essentially insoluble in the liquid medium. Representative liquid media include an aqueous medium. Using the process of the present invention the average particle size of coarse compound (I) may be up to 1 mm in diameter. This advantageously avoids the need to pre-process the compound.
In a further aspect of the invention the aqueous medium to be subjected to the milling comprises compound (I) present in from about 1% to about 40% w/w, preferably from about 10% to about 30% w/w, more preferably about 20% w/w.
The aqueous medium may further comprise one or more pharmaceutically acceptable water- soluble carriers which are suitable for steric stabilisation and the subsequent processing of compound (I) after milling to a pharmaceutical composition, e.g. by spray drying. Pharmaceutically acceptable excipients most suitable for steric stabilisation and spray-drying are surfactants such as poloxamers, sodium lauryl sulphate and polysorbates etc; stabilisers such as celluloses e.g. hydroxypropylmethyl cellulose; and carriers such as carbohydrates e.g. mannitol.
In a further aspect of the invention the aqueous medium to be subjected to the milling may further comprise hydroxypropylmethyl cellulose (HPMC) present in from about 0.1 to about 10% w/w, preferably in about 5% w/w in the aqueous medium to be subjected to the milling. In a further aspect of the invention the aqueous medium to be subjected to the milling may further comprise hydroxypropylmethyl cellulose (HPMC) present in about 3% w/w or 1% w/w.
In a further aspect of the invention the aqueous medium to be subjected to the milling may further comprise mannitol present in from about 1 to about 15% w/w, preferably in about 10% w/w, in the aqueous medium to be subjected to the milling.
In a further aspect of the invention the aqueous medium to be subjected to the milling may further comprise sodium lauryl sulphate present in about 0.2% w/w.
The process of the present invention may comprise the subsequent step of drying compound (I) to yield a powder.
Accordingly, in a further aspect, the present invention provides a process for preparing a pharmaceutical composition as hereinbefore defined, which process comprises producing compound (I) in nanoparticulate form optionally followed by drying to yield a powder.
By "drying" is meant the removal of any water or other liquid vehicle used during the process to keep compound (I) in liquid suspension or solution. This drying step may be any process for drying known in the art, including freeze drying, spray granulation or spray drying. Of these methods spray drying is particularly preferred. All of these techniques are well known in the art. Spray drying/fluid bed granulation of milled compositions is carried out most suitably using a spray dryer such as a Mobile Minor Spray Dryer [Niro, Denmark], or a fluid bed drier, such as those manufactured by Glatt, Germany.
In a further aspect the invention provides a pharmaceutical composition as hereinbefore defined, in the form of a dried powder, obtainable by wet milling solid particles of compound (I) followed by spray-drying the resultant suspension.
Preferably, the pharmaceutical composition as hereinbefore defined, further comprises HPMC present in less than 15% w/w, preferably in the range 0.1 to 10% w/w, more preferably in about 5% w/w.
Preferably, the pharmaceutical composition as hereinbefore defined, further comprises HPMC present in about 3% w/w or 8% w/w. Preferably the pharmaceutical composition as hereinbefore defined, in the form of a dried powder, further comprises mannitol present in less than 30% w/w, preferably in the range 1 to 15% w/w, more preferably in about 10% w/w.
Preferably, the pharmaceutical composition as hereinbefore defined, in the form of a dried powder, further comprises mannitol present in the range 30 to 45% w/w, more preferably in about 34% w/w or 43% w/w.
Preferably, the pharmaceutical composition as hereinbefore defined, in the form of a dried powder, further comprises sodium lauryl sulphate present in about 0.6% w/w.
Preferably the pharmaceutical composition as hereinbefore defined, in the form of a dried powder, further comprises HPMC present in less than 15% w/w, preferably in the range 0.1 to 10% w/w, and mannitol present in less than 30% w/w, preferably in the range 1 to 15% w/w.
Preferably the pharmaceutical composition as hereinbefore defined, in the form of a dried powder, further comprises HPMC present in about 3% w/w, mannitol present in the range 30 to 45% w/w, more preferably in about 34% w/w, and sodium lauryl sulphate present in about 0.6% w/w.
The solid particles of compound (I) obtainable by wet milling, optionally followed by the step of spray-drying, according to the present invention, may be presented in a variety of finished formulations including, for instance, tablets, for example swallow tablets, dispersible tablets and chewable tablets; in capsules; aqueous syrups and sachets. These may be prepared by combining the pharmaceutical composition of the present invention with excipients conventionally used in such formulations such as disintegrants, diluents, lubricants, wetting agents, binding agents, flavoring agents, sweeteners, colouring agents, preservatives, suspending agents, coating agents and fillers, and further processing into finished formulations. Thus, in a further aspect, pharmaceutical formulations of the present invention comprise pharmaceutical compositions as hereinbefore defined, optionally together with one or more excipients such as disintegrants, diluents, lubricants, wetting agents, binding agents, flavoring agents, sweeteners, colouring agents, preservatives, suspending agents, coating agents and fillers.
Representative disintegrants for use in the instant invention illustratively include maize-starch and rice starch, cross-linked N-vinyl-2-pyrrolidinone, sodium starch glycollate, croscarmellose sodium, micrcrystalline or microfine cellulose, low substitued hydroxypropylcellulose (i.e. cellulose partially substitued with 2-hydroxypropyl groups e.g. less than 25% substituted) cross- linked sodium carboxymethylcellulose, swellable ion exchange resins, formaldehyde-casein or alignates.
Representative lubricants for use in the instant invention illustratively include a long chain fatty acid, such as stearic acid, or salts thereof, such as magnesium stearate.
Representative fillers for use in the instant invention illustratively include silicon dioxide, microcrystalline cellulose, dicalcium phosphate, lactose, sorbitol, cacium carbonate or magnesium carbonate.
In another aspect the invention provides a pharmaceutical composition comprising compound (I) in a form which results in a pharmacokinetic profile in a healthy male volunteer study wherein the median Tmax is in the range 0J5 to 1.25 hours, the median Cmax is in the range 130 to 170 ng/mL and the AUC (last) is in the range 800 to 900 ng/mL.h.
In another aspect the invention is directed to a method of treating a human or animal subject suffering from a condition which is mediated by COX-2 which comprises administering a pharmaceutical composition comprising compound formula (I) or a pharmaceutically acceptable salt thereof in which the compound is present in solid particles in nanoparticulate form.
In another aspect the invention is directed to the use of a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof in which the compound is present in solid particles in nanoparticulate form for the manufacture of a medicament for the treatment of a condition which is mediated by COX-2.
All publications and references, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference in their entirety as if each individual publication or reference were specifically and individually indicated to be incorporated by reference herein as being fully set forth.
The example that follows illustrates the invention but does not limit the invention in any way.
Example 1 (Pharmaceutical Composition 2) A 1 kg batch of an aqueous suspension containing 20% w/w of 2-(4-ethoxy-phenyl)-3-(4- methanesulfonyl-phenyl)-pyrazolo[1 ,5-b]pyridazine and 5% w/w of hydroxypropylmethylcellulose was passed through a Dena DM-100 bead mill. The single 100ml chamber fabricated from Nylacast Nylube was used in a recirculation configuration with the chamber containing 85% by volume of yttrium stabilised zirconium oxide beads (Tosoh, Japan). The batch was processed using four different bead sizes in sequence: 1mm diameter bead sample, 0.65mm diameter bead sample, 0.4mm diameter bead sample, 0.3mm diameter bead sample. The batch was processed for one hour using each bead sample. The yield was 81.3%. To the finely milled suspension was added 10% w/w mannitol and the resulting suspension subsequently spray- dried to yield Pharmaceutical Composition 2.
Grinding media contamination levels in the spray-dried powder (Pharmaceutical Composition 2) were 7ppm zirconium (Zr) and <1ppm yttrium (Y).
The product had a median particle size of 1.01 microns as measured by laser diffraction size analysis using a Sympatec laser diffraction unit, with a HELOS optical bench fitted with a QUIXEL dispersion unit.
Example 2
A 5 kg batch of an aqueous suspension containing 20% w/w of 2-(4-ethoxy-phenyl)-3-(4- methanesulfonyl-phenyl)-pyrazolo[1 ,5-b]pyridazine, 0.2% w/w of sodium lauryl sulphate and 1% w/w of hydroxypropylmethylcellulose was passed through a Drais Cosmo 5 bead mill. The single 500ml chamber fabricated from Sustaplast Nylon 6G was used in a recirculation configuration with the chamber containing 570 mL of yttrium stabilised zirconium oxide beads (Tosoh, Japan). The batch was processed using two different bead sizes in sequence: 0.8 mm diameter bead sample and a 0.3 mm diameter bead sample. The batch was processed for 23 minutes for the larger bead size and 80 minutes for the smaller bead size. The yield was 90%. To the finely milled suspension was added 10% w/w mannitol and the resulting suspension subsequently spray-dried to yield Example 2.
The product had a median particle size of 0.8 microns as measured by laser diffraction size analysis using a Sympatec laser diffraction unit, with a HELOS optical bench fitted with a QUIXEL dispersion unit.
Study 1
A randomised, open label, crossover comparison between single oral doses of 35mg of each of two pharmaceutical compositions of 2-(4-ethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)- pyrazolo[1 ,5-b]pyridazine was conducted in 24 healthy male volunteers. Single oral doses of 35mg of each of two pharmaceutical compositions of 2-(4-ethoxy-phenyl)-3-(4-methanesulfonyl- phenyl)-pyrazolo[1 ,5-b]pyridazine were administered to fasted volunteers. Seven day intervals separated each dose. The pharmacokinetic characteristics of each pharmaceutical composition were determined over a 48 hour time period.
Pharmaceutical Composition 1 - Amorphous spray-dried pharmaceutical composition comprising 2-(4-ethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1 ,5-b]pyridazine and hydroxypropylmethylcellulose-acetyl succinate in a 1 :1 ratio produced by conventional spray- drying techniques.
Pharmaceutical Composition 2 - as for Example 1 above
Table 1 : Summary of Median Serum Derived Pharmacokinetic Parameters for Pharmaceutical Compositions 1 and 2 of 2-(4-Ethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1 ,5- bjpyridazine from a Healthy Male Volunteer Study of 24 Subjects.
Graph 1 :
A Graphical Representation comparing the inter- subject variability of Pharmaceutical Compositions 1 and 2 seen on measuring AUC last
mm max
—Median
Pharmaceutical Pharmaceutical
Composition 1 Composition 2
Pharmaceutical Composition Graph 2:
A Graphical Representation comparing the inter- subject variability of Pharmaceutical Compositions 1 and 2 seen on measuring T max
mm max
—Median
Pharmaceutical Pharmaceutical
Composition 1 Composition 2
Pharmaceutical Composition
Graph 3:
A Graphical Representation comparing the inter- subject variability of Pharmaceutical Compositions 1 and 2 seen on measuring C max
mm max
—Median
Pharmaceutical Pharmaceutical
Composition 1 Composition 2
Pharmaceutical Composition

Claims

Claims
1. A pharmaceutical composition comprising compound (I)
and pharmaceutically acceptable salts thereof, in which the compound is present in solid particles in nanoparticulate form in admixture with one or more pharmaceutically acceptable carriers or excipients.
2. A pharmaceutical composition as claimed in claim 1 which further comprises HPMC present in less than 15% w/w.
3. A pharmaceutical composition as claimed in claim 1 or claim 2 which further comprises mannitol present in the range 30 to 45% w/w.
4. A pharmaceutical composition as claimed in any of claims 1 to 3 which further comprises sodium lauryl sulphate present in about 0.6% w/w.
5. A process for preparing a pharmaceutical composition according to any of claims 1 to 4 comprising wet milling a suspension of compound (I) in a mill having at least one chamber and agitation means, said chamber(s) and/or said agitation means comprising a lubricated nylon.
4. A method of treating a human or animal subject suffering from a condition which is mediated by COX-2 which comprises administering a pharmaceutical composition as defined in any of claims 1 to 4.
5. The use of a pharmaceutical composition as defined in any of claims 1 to 4 for the manufacture of a medicament for the treatment of a condition which is mediated by COX-2.
EP03706615A 2002-03-15 2003-03-13 Pharmaceutical compositions comprising 2-(4-ethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo¬1,5-b|pyridazine in nanoparticulate form Expired - Lifetime EP1485098B1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GBGB0206200.8A GB0206200D0 (en) 2002-03-15 2002-03-15 Pharmaceutical compositions
GB0206200 2002-03-15
PCT/EP2003/002698 WO2003077920A1 (en) 2002-03-15 2003-03-13 Pharmaceutical compositions comprising 2-(4-ethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo’1,5-bipyridazine in nanoparticulate form

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EP1485098A1 true EP1485098A1 (en) 2004-12-15
EP1485098B1 EP1485098B1 (en) 2007-01-03

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AT (1) ATE350038T1 (en)
AU (1) AU2003208709A1 (en)
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GB (2) GB0206200D0 (en)
IS (1) IS7378A (en)
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NO (1) NO20043889L (en)
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US7235560B2 (en) 2002-08-19 2007-06-26 Glaxo Group Limited Pyrimidine derivative as selective COX-2 inhibitors
GB0221443D0 (en) 2002-09-16 2002-10-23 Glaxo Group Ltd Pyridine derivates

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US5145684A (en) * 1991-01-25 1992-09-08 Sterling Drug Inc. Surface modified drug nanoparticles
YU11900A (en) * 1997-09-05 2002-11-15 Glaxo Group Limited 2,3-diaryl-pyrazolo (1,5-b)pyridazines derivatives their preparation and their use as cyclooxygenase 2(cox-2) inhibitors
SK12672001A3 (en) * 1999-12-08 2002-04-04 Pharmacia Corporation Compositions of cyclooxygenase-2 inhibitor having rapid onset of therapeutic effect
CN1321628C (en) * 2000-06-28 2007-06-20 史密斯克莱·比奇曼公司 Wet milling process

Non-Patent Citations (1)

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Title
See references of WO03077920A1 *

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ZA200406553B (en) 2005-09-22
DE60310896D1 (en) 2007-02-15
EA200400864A1 (en) 2005-02-24
KR20040091133A (en) 2004-10-27
GB2402335B (en) 2005-10-12
PL372932A1 (en) 2005-08-08
GB2402335A (en) 2004-12-08
JP2005520824A (en) 2005-07-14
NO20043889L (en) 2004-09-16
AU2003208709A1 (en) 2003-09-29
GB0206200D0 (en) 2002-05-01
NZ534179A (en) 2006-07-28
EA007201B1 (en) 2006-08-25
DE60310896T2 (en) 2007-05-10
BR0307427A (en) 2004-12-28
US20050153967A1 (en) 2005-07-14
ATE350038T1 (en) 2007-01-15
GB0419971D0 (en) 2004-10-13
WO2003077920A1 (en) 2003-09-25
IS7378A (en) 2004-07-29
EP1485098B1 (en) 2007-01-03
CA2478758A1 (en) 2003-09-25
MXPA04009008A (en) 2004-12-07
ES2277634T3 (en) 2007-07-16
ECSP045295A (en) 2004-10-26

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